ABCMdb

PMID: 17312388

Li J, Cusatis G, Brahmer J, Sparreboom A, Robey RW, Bates SE, Hidalgo M, Baker SD
Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients.
Cancer Biol Ther. 2007 Mar;6(3):432-8. Epub 2007 Mar 29., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCG2 p.Gln141Lys Jude Children's Research Hospital; 332 North Lauderdale Street, DTRC Room D1034, Mail Stop 314; Memphis, Tennessee USA 38105; Tel.: 901.495.3089; Fax: 901.495.3125; Email: sharyn.baker@stjude.org Original manuscript submitted: 12/21/06 Manuscript accepted: 12/29/06 Previously published online as a Cancer Biology & Therapy E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=3763 Key words gefitinib, erlotinib, EGFR tyrosine kinase inhibitor, ABCG2, polymorphism, pharmacokinetics Abstract The purpose of the study was to determine if the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, are substrates for the efflux transporter ABCG2, and to investigate the relevance of the ABCG2 421C>A (Q141K) polymorphism to the pharmacokinetics of gefitinib. Login to comment 2 ABCG2 p.Gln141Lys Gefitinib and erlotinib transport in vitro was studied using HEK293 cells transfected with ��wild‑type ABCG2 or a Q141K clone. Login to comment 12 ABCG2 p.Gln141Lys In particular, a functional single nucleotide polymorphism has been recently identified in exon 5 of the ABCG2 gene, in which a C>A nucleotide transition at position 421 (ABCG2 421C>A) results in a non-synonymous variant protein with a glutamine to lysine amino acid substitution in codon 141 (Q141K).19 The ABCG2 421C>A variant has been associated with low ABCG2 expression levels and altered substrate specificity,19 and has been found to alter the pharmacokinetics of diflomotecan and topotecan.13,24 Recently developed tyrosine kinase inhibitors, including imatinib and gefitinib, have been shown to inhibit ABCG2,25‑29 and imatinib has been shown to be a substrate for ABCG2.5 The aim of this study was to determine if ��ABCG2 transports the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib, ��by examining cellular accumulation and efflux in human embryonic kidney cells (HEK293) transfected with empty vector, wild‑type ABCG2 and a 421C>A variant clone. Login to comment 71 ABCG2 p.Gln141Lys Comparative intracellular accumulation of 3H-gefitinib (A) and erlotinib (B) in human embryonic kidney cells (HEK293) transfected with a pcDNA3 vector (pcDNA3), wild-type (R-5), and Q141K variant (Q141-K5) of ABCG2. Login to comment 74 ABCG2 p.Gln141Lys *, ANOVA, significantly different from the control (pcDNA3), P<0.05; **, ANOVA, significantly different from the control (pcDNA3) and Q141 variant (Q141-K5), P<0.05 Table 1 Kinetic parameters a for cellular efflux of 3H‑gefitinib by �� HEK293 transfected with pcDNA3 vector (pcDNA), Q141K variant (Q141‑K5), and wild‑type (R‑5) of ABCG2, ��at the drug concentrations of 1 and 10 mM Gefitinib 1 mM Gefitinib 10 mM Emax (%) ET50 (h) Emax (%) ET50 (h) pcDNA 19.5 ± 4.19 1.40 ± 0.69 22.7 ± 10.6 1.86 ± 1.57 Q141‑K5 22.1 ± 2.23* 0.74 ± 0.09* 22.7 ± 2.30 1.00 ± 0.26 R‑5 27.3 ± 1.26*† 0.67 ± 0.09* 25.2 ± 4.04 1.13 ± 0.39 aIndividual cellular efflux curves were fitted with Michaelis‑Menten equation, where Emax is the maximum efflux fraction (%initial radioactivity), and ET50 is the time to achieve the half‑Emax. Login to comment 98 ABCG2 p.Gln141Lys Relative intracellular accumulation of 3H-gefitinib (A) and erlotinib (B) in human embryonic kidney cells (HEK293) transfected with a pcDNA3 vector (pcDNA3), wild-type (R-5), and Q141K variant (Q141-K5) of ABCG2, in the absence and presence of 1 µM or 5 µM of the ABCG2 specific inhibi� tor fumitremorgin (FTC). Login to comment 101 ABCG2 p.Gln141Lys *, ANOVA, significantly different from the control (in the absence of FTC), P<0.05 Table 2 Genotype and allele frequencies for the studied variant genes Genotype Frequenciesa Allele Frequenciesb Variantc Effectd Activitye Wt Het Var p q ABCB1 3435C > T I1145I (exon 26) Decreased 7 (26%) 12 (44%) 8 (30%) 0.48 0.52 ABCG2 421C > A Q141K (exon 5) Decreased 20 (74%) 7 (26%) 0 (0) 0.87 0.13 aNumber represents number of patients with percentage in parenthesis. Login to comment 110 ABCG2 p.Gln141Lys Cellular efflux of 3H-gefitinib (A and B) and erlotinib (C and D) by human embryonic kidney cells (HEK293) transfected with a pcDNA3 vector (pcDNA3), wild-type (R-5), and Q141K variant (Q141-K5) of ABCG2, after cells were pre-incubated with 1 µM (A and C), and 10 µM (A and D) of the drug (i.e., gefitinib or erlotinib) for 1 h. Login to comment